Altering Temperature in a Mammalian Body

ABSTRACT

The present application relates to systems and methods for altering temperature in a mammalian body. Optionally, the systems and methods can be used to lower or raise core body temperature of a mammalian subject. Optionally, the systems and methods can be used to lower or raise the temperature of glabrous skin of a mammalian subject.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional PatentApplication No. 61/276,764, filed Sep. 16, 2009 and U.S. ProvisionalPatent Application No. 61/276,787, filed Sep. 16, 2009, both of whichare incorporated herein by reference in their entirety.

TECHNICAL FIELD

The present application relates to systems and methods for alteringtemperature in a mammalian body. Optionally, the systems and methods canbe used to lower or raise core body temperature of a mammalian subject.Optionally, the systems and methods can be used to lower or raise thetemperature of glabrous skin of a mammalian subject.

BACKGROUND

The thermoregulatory system of homeotherms has an inherent ability tohold core body temperature within a small variation of a set point.Excursions, above and below the set point can cause compromised bodyfunction, injury, and even death may occur.

Operation of the thermoregulatory system is based on a complex,nonlinear network of feedback control signals and responses to adjustthe thermal resistance between the body core and the environment and tomodulate the rate and distribution of internal energy generation. Theoperation of this system is remarkably efficient over a broad spectrumof physiological states and environmental conditions.

In certain circumstances, however, the thermoregulatory system is unableto maintain the core temperature within the set operational range, orthere may be therapeutic or prophylactic reasons to override the systemto cause changes in the core temperature beyond the normal range. Thereare also situations where it may be desirable to alter the temperatureof portions of the body other than the body's core. For example, it maybe desirable to alter the temperature of glabrous skin in a subject.

SUMMARY

The present application relates to systems and methods for alteringtemperature in a mammalian body. Optionally, the systems and methods canbe used to lower or raise core body temperature of a mammalian subject.Optionally, the systems and methods can be used to lower or raise thetemperature of glabrous skin of a mammalian subject.

For example, provided are methods for increasing or maintainingtemperature of glabrous tissue in a subject. Also provide are methodsfor cooling the core body temperature of a subject. Further provided aremethods for warming the core body temperature of a subject.

The methods include applying heat to peripheral thermoregulatory controltissue of the subject. The applied heat increases or maintains perfusionof blood in the glabrous tissue. By increasing or maintaining perfusion,the temperature of the glabrous tissue can be optionally increased. Insome aspects, cooling stimulus can be applied to the glabrous tissuewith the increased or maintained perfusion. In other aspects, a warmingstimulus can be applied the glabrous tissue with the increased ormaintained perfusion. When a cooling stimulus is used, the coretemperature of the subject can be reduced. When a warming stimulus isused, the core temperate of the subject can be increased.

Optionally, the peripheral thermoregulatory control tissue is located inthe cervical spinal region or in the lumbar spinal region of thesubject. Negative pressure can also be applied to the glabrous tissue.The negative pressure can be used to increase or maintain perfusion ofblood in the glabrous tissue.

For the core cooling methods, the subject may have sufferedcardiopulmonary arrest, ischemic stroke, subarachnoid hemorrhage,hepatic encephalopathy, trauma, brain surgery, perinatal asphyxia,infantile encephalitis, a hyperthermic-inducing event, or acute braininjury. With these conditions, the methods can be used to cool the corebody temperature and to establish hypothermia in the subject. For thewarming methods, the subject may have suffered a hypothermia-inducingevent.

Also provided are systems for cooling the core body temperature of asubject. The systems include a heating device configured to apply heatto peripheral thermoregulatory control tissue of the subject. Theapplied heat increases or maintains perfusion of blood in the glabroustissue. The systems further comprise a cooling device configured toapply a cooling stimulus to the glabrous tissue and may optionallycomprise a device adapted to apply negative pressure to the glabroustissue.

The heating device can be adapted to deliver heat to the cervical spinalregion and/or lumbar spinal region of the subject. Optionally, theheating device is configured to heat the skin overlying the peripheralthermoregulatory control tissue of the subject. Optionally, the heatingdevice is configured to heat the tissue below the skin overlying theperipheral thermoregulatory control tissue of the subject. The heatingdevice can be optionally selected from the group consisting of aresistive heating device, an electromagnetic based heating device, alight based heating device, an ultrasound based heating device, and anexothermic chemical reaction based heating device. The cooling devicecan be adapted to provide a cooling stimulus to a palmar and/or to aplantar region and/or to an area of glabrous skin on the face of thesubject. Optionally, the cooling device comprises a liquid that iscooled to a temperature lower than the glabrous tissue.

Also provided are systems for warming the core body temperature of asubject. The systems include a heating device configured to apply heatto peripheral thermoregulatory control tissue of the subject. Theapplied heat increases or maintains perfusion of blood in the glabroustissue. The systems further comprise a warming device configured toapply a warming stimulus to the glabrous tissue and may optionallycomprise a device adapted to apply negative pressure to the glabroustissue.

The heating device can be adapted to deliver heat to the cervical spinalregion and/or the lumbar spinal region of the subject. Optionally, theheating device is configured to heat the skin overlying the peripheralthermoregulatory control tissue of the subject. Optionally, the heatingdevice is configured to heat the tissue below the skin overlying theperipheral thermoregulatory control tissue of the subject. The heatingdevice can be optionally selected from the group consisting of aresistive heating device, an electromagnetic based heating device, alight based heating device, an ultrasound based heating device, and anexothermic chemical reaction based heating device. The warming devicecan be adapted to provide a warming stimulus to a palmar and/or to aplantar region and/or to an area of glabrous skin on the face of thesubject. Optionally, the warming device can be selected from the groupconsisting of a resistive heating device, an electromagnetic basedheating device, a light based heating device, an ultrasound basedheating device, and an exothermic chemical reaction based heatingdevice.

These and other features and advantages of the present invention willbecome more readily apparent to those skilled in the art uponconsideration of the following detailed description and accompanyingdrawings, which describe both the preferred and alternative embodimentsof the present invention.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a schematic illustration of an example system for alteringtemperature in a mammalian body.

FIG. 2A is a schematic illustration of an example system for alteringtemperature in a mammalian body.

FIG. 2B is a schematic cross sectional illustration of the coolingdevice 301 of FIG. 2A taken across the line 2B-2B.

FIG. 3A is a schematic illustration of heat application to the cervicalspinal thermoregulatory tissue of a subject.

FIG. 3B is a schematic illustration of a device for heat application tothe cervical spinal thermoregulatory tissue of a subject.

FIG. 4 is a schematic illustration showing aspects of an example systemfor cooling or heating the core temperature of a mammalian subject.

FIG. 5 is a flow diagram showing example methods for alteringtemperature in a mammalian subject.

FIGS. 6A and 6B are schematic illustrations showing aspects of theexample system of FIG. 4.

FIG. 7 is a schematic illustration of aspects of a system for alteringtemperature in a mammalian body.

FIG. 8 is a schematic illustration of aspects of a system for alteringtemperature in a mammalian body.

FIG. 9 is a schematic illustration of aspects of a system for alteringtemperature in a mammalian body.

FIG. 10 is a schematic illustration of aspects of a system for alteringtemperature in a mammalian body.

FIG. 11 is a schematic illustration of aspects of a system for alteringtemperature in a mammalian body.

FIG. 12 is a schematic illustration of aspects of a system for alteringtemperature in a mammalian body.

FIG. 13 is a schematic illustration of aspects of a system for alteringtemperature in a mammalian body.

FIG. 14 is a schematic illustration of aspects of a system for alteringtemperature in a mammalian body.

FIG. 15 is a graph showing the effect of application of negativepressure on blood perfusion in a hand.

FIG. 16 is a graph showing the temperature of a hand over time.

FIG. 17 is a graph showing increase in blood perfusion in a hand as afunction of applied negative pressure.

FIG. 18 is a graph showing thermal flux, pressure and temperature overtime.

FIG. 19 illustrates graphs showing increase in blood flow to palmararteriovenous anastomoses (AVAs) by cervical heating and temperature ofthe neck of a subject.

FIG. 20 illustrates graphs showing increase in blood flow to plantararteriovenous anastomoses (AVAs) by cervical heating and temperature ofthe neck of a subject.

FIG. 21 is a graph illustrating temperature of spine skin andtemperature of a hand over time.

FIG. 22 is a graph illustrating temperature of spine skin and plantartemperature over time.

FIG. 23 illustrates graphs showing warming of glabrous skin viaincreased blood flow through glabrous tissues of the hand and bloodperfusion of glabrous skin over time.

FIG. 24 illustrates graphs showing core cooling via cervical heating inconjunction with palmar and plantar cooling, the temperature of the neckover time and the temperature of the palm over time.

Like reference numbers and designations in the various drawings indicatelike elements.

DETAILED DESCRIPTION

The present invention now will be described more fully hereinafter withreference to specific embodiments of the invention. Indeed, theinvention can be embodied in many different forms and should not beconstrued as limited to the embodiments set forth herein; rather, theseembodiments are provided so that this disclosure will satisfy applicablelegal requirements.

Mammalian body temperature is tightly regulated by an internal autonomicregulatory system which comprises central controllers and the bloodcirculatory system, plus mechanisms for adjusting the rate and locationsof internal energy generation. The circulatory system covers the entirebody and delivers heat from the body core to the peripheral areas, or,in less frequent circumstances, delivers heat from the periphery to thecore.

Alteration of the blood flow through the skin plays an important role intemperature regulation. For example, in nonglabrous skin vasodilation(dilation of arterioles and small arteries) and vasoconstriction(constriction of arterioles and small arteries) increase or decreaseblood flow to match thermoregulatory needs. Both the processes ofvasoconstriction and vasodilation are regulated by active means inresponse to a combination of local, systemic, and central inputs.

Normally, when body and/or environmental temperatures are high,vasodilation favors high blood flow to the surface areas involved withheat exchange, thus increasing heat loss to the environment andreduction in the deep body core region temperature. As environmentaland/or body temperatures fall, vasoconstriction reduces blood flow tothe skin surfaces and minimizes heat loss to the environment.

One important effector of the thermoregulatory system is controlled byblood flow to specialized skin areas of the body at non-hairy skinsurfaces, also referred to as glabrous skin, and includes skin at thepalms of the hands, soles of the feet, and the ears, cheeks, forehead,and nose regions or any area of skin that contains a special vascularstructure that is effective in affecting heat transfer betweencirculating blood and the body surface. Basal to the skin in these areasare unique anatomical vascular structures called venous plexuses. Thesestructures serve to deliver large volumes of blood adjacent to the skinsurface under conditions of vasodilation. By this delivery of blood,significant heat transfer may occur for the maintenance of internalorgans within a functional temperature range.

Blood is permitted to pass through the venous plexus structures by wayof arteriovenous anastamoses (AVAs) that are blood vessels that directlyshunt arterial blood to the veins without passing through thecapillaries. When vasodilated, the AVAs have a diameter an order ofmagnitude or greater than the capillaries, thereby providing a low flowresistance pathway for blood circulating from the heart. At fullvasodilation the AVAs present among the lowest flow resistance of theentire circulatory system, resulting in a considerable fraction of thetotal cardiac output flowing through them. The relative proximity of thecutaneous AVAs to the surface of the body, and the potential forcarrying large rates of blood flow make the AVAs a very effective heatexchange vehicle in the thermoregulatory apparatus. The AVAs are anintegral part of the body's heat transfer system, providing importantthermoregulatory control. Regulation of the AVA flow diameter is uniquein comparison to the cutaneous microcirculation in nonglabrous skin.Adjustment in the flow resistance through AVAs is controlled byactivation and relaxation of vasoconstriction.

Thermal stimulation of the peripheral thermoregulatory control tissuecan cause an increase in the mean value of AVA flow wherein thevasomotive fluctuations are superimposed at a higher average flow.Removal of the thermal stimulation of the peripheral thermoregulatorycontrol tissue can result in a lowering of the mean AVA flow as therelaxing input to the AVA vasoconstriction activity is diminished. Thisdirect coupling between thermal stimulation of peripheralthermoregulatory control tissue and AVA perfusion rate offers a powerfulopportunity to manipulate convective heat transfer processes involvingglabrous skin, including convective movement of energy between the bodysurface and core via the circulation of blood to and from the AVAs,without involving inputs from the thermoregulatory control tissue of thehypothalamus

The operation of this system is remarkably efficient over a broadspectrum of physiological states and environmental conditions. Incertain circumstances, however, the thermoregulatory system is unable tomaintain the core temperature within the set operational range, or theremay be therapeutic or prophylactic reasons to override the system tocause changes in the core temperature beyond the normal range. In thesecases, devices and methods are applied interventionally either to assistor to override the thermoregulatory system.

A different challenge in regulating the body core temperature arisesunder conditions for which the brain becomes starved of oxygen owing toa medical event such as cardiac arrest, stroke, or traumatic braininjury. Laboratory and clinical data indicate that if the body core, andparticularly the brain, temperature can be reduced by as little as 2° C.within approximately 90 minutes of the precipitating event, asignificant therapeutic benefit is realized to limit mortality andmorbidity. Unfortunately, the function of the thermoregulatory systemresists lowering the core temperature from a state of normothermia viacutaneous vasoconstriction to increase the thermal resistance betweenthe skin and core and by shivering to increase the rate of internalmetabolic heat generation.

An example is the use of therapeutic hypothermia to treat a subject whois suffering an episode of brain ischemia that may be caused by stroke,cardiac arrest, traumatic brain injury, or another condition. Such asubject may be in an initial state of AVA vasoconstriction. At thistime, when therapeutic hypothermia is applied within a short time windowof efficacy, according to the methods of the disclosure, a state of AVAvasodilatation is induced on demand. For example, using the describedmethods, systems and devices therapeutic hypothermia can be induced in asubject at about 90 minutes or less following an insult to a subjectthat would benefit from therapeutic hypothermia. For example, followingan insult to the brain, heart or other tissue, therapeutic hypothermiacan be induced at about 90 minutes or less from the insult.

Surface cooling over large areas of skin is ineffective because itinduces vasoconstriction, thereby eliminating direct circulation ofblood between the skin and core, which is a much more effective heattransfer mechanism than parasitic conduction through the bodystructures. Alternatively, methods have been developed for cooling thecore directly by infusion of large volumes of chilled saline solutioninto the circulatory system. Collateral drawbacks associated with thistechnology include the necessity of canulating the circulatory systemunder sterile conditions and introduction of added volume of fluid intothe blood which can result in elevated blood pressure. Since thistechnology is typically practiced in a medical facility, precious timeduring the window of therapeutic opportunity (approximately 90 minutes)is lost during transport following the precipitating event to a medicalfacility and the initiation of therapy. The systems and methodsdescribed herein can be used to produce a state of therapeutichypothermia on demand following a brain ischemia producing event within90 minutes.

Another thermoregulatory challenge occurs when a person is hypothermicwith a necessity of being rewarmed to normotheria in the absence ofconditions such as anesthesia that would result in a state ofvasodilation in the cutaneous circulation. The most effective heattransport mechanism to warm the body core is by the circulation of bloodbetween the skin and the core. However, hypothermia-induced cutaneousvasoconstriction blocks this mechanism. The systems and methodsdescribed herein bypass this state to gain convective access to the bodythermal core for warming.

A further need arises when a person is subjected to a cold environmentfor a period of time sufficient to elicit vasoconstriction of the AVAs,particularly in the hands and feet. Although this standardthermoregulatory response is conservative of the body's core energy andis important for long term survival, in the short term it creates acondition of discomfort, with a strong sensation of having cold handsand feet. Typical responses are: to adopt behaviors to attempt to warmthe hands and feet; to provide increased insulation surrounding thehands and feet; and/or to apply various devices to actively warm thehands and feet. However, these measures are not generally effective inthe short term since they do not address the source of cold sensation,that being vasoconstriction of AVAs.

The described methods and devices can be used to trigger the opening ofvasoconstricted AVAs on demand, in the absence of extreme localconditions that may override all other control signals, to produce ahigh level of blood perfusion through glabrous skin. Vasodilation of thevasoconstricted, or more mechanistically, relaxation of thevasoconstriction of AVAs, enables the resolution of all of the foregoingthermal physiological challenges.

Referring to FIG. 1 an example system 200 is illustrated. The system 200can be used to heat or cool a mammal's core temperature. The system canalso be used to heat or cool glabrous tissue of a mammal.

The system 200 includes a heating element 202, also referred to as aheating device. The heating element 202 can comprise any device that canbe used to heat skin and/or underlying tissues of a mammalian body. Forexample, the heating element may comprise a resistive heating elementand thus act as a traditional heating pad when supplied with electricalcurrent. In this regard, the heating element 202 can receive currentfrom a power source 232. The heating element 202, however, is notlimited to a resistive heating device, such as a heating pad.

The heating element 202 can be any device that can raise the temperatureof a mammal's skin and/or the tissues underlying the skin of a mammal'sbody. One skilled in the art will therefore appreciate that manyalternative heating elements can be used. Several other non-limitingexamples include exothermic chemical reactions, application ofelectromagnetic energy, light, ultrasound or other energy to theskin/underlying tissues. Thus, many different devices and process may beapplied for heating the peripheral thermoregulatory control tissue toraise its temperature to a degree wherein the level of stimulationreaches the threshold requisite to cause relaxation of thevasoconstrictive effect on AVAs in glabrous skin. Example heatingdevices use surface delivery of heat to the skin. Other example heatingdevices use deep tissue delivery of heat.

The increase in temperature caused by the heating element can bemeasured and/or monitored by a temperature sensing device 216. Thetemperature sensing device 216 can be positioned in proximity to theheating element 202 such that it can optionally determine temperatureinformation including, for example, if the temperature of the skin orunderlying tissues has been increased, the extent of such increase, andany temporal fluctuations in temperature in the skin or tissuesproximate the heating element. Optionally, temperature information canbe communicated to a temperature sensing module 244 of a computer 224.The temperature information can be processed, for example, using theprocessor 226 and such processed information can be used to regulate theintensity of heat and duration of heat produced by the heating element.For example, the power module 232 can also be in operative communicationwith the processor 226 and the temperature information can be used toincrease or decrease the power supply to the heating element 202.

Heat from the heating element 202 can be used to trigger, on demand, therelaxing of vasoconstriction of AVAs in glabrous skin. There arenumerous benefits of increased AVA perfusion such as gaining access tocutaneous blood flow for convective heat transfer of blood with heatingand cooling sources placed on the surface of the skin to provideefficient transport of energy between the body core and the bodyexterior surface via the circulation of blood. Another benefit ofincreased AVA perfusion from a state of vasoconstriction is the addedheat transfer to the skin from warm blood circulating from the bodycore, thereby reducing or eliminating a feeling of coldness experiencedin vasoconstricted glabrous skin of the hands and feet, which may beperceived as being uncomfortable.

A method for causing AVAs to vasodilate is to apply a heating source totissues at a site of thermoregulatory control that is peripheral to thepreoptic hypothalamus. Thus, thermal stimulation of peripheralthermoregulatory control tissue via heating by multiple alternativemeans include, but are not limited to, (a) a heat source applied to thesurface of the skin, (b) deep heating via an infrared source, (c) deepheating via an electromagnetic source such as in diathermy, and (d) deepheating via an ultrasound source. Peripheral thermoregulatory tissueincludes tissue that when heated exerts control on AVAs and does notinclude the brain and hypothalamus.

FIGS. 3A and 3B show that among peripheral areas that can be heated forthis purpose is that tissue of and proximal to the spinal cord,including the cervical and lumbar areas that are rich in parasympatheticinnervation. FIG. 3A illustrates a cross sectional view of the spine andoverlying tissues during heating to stimulate blood flow through thearteriovenous anastomoses by which a heating source 202 is appliedeither to the skin surface or by a penetrating mechanism to reach deepertissues through the skin and toward the spine to produce an elevatedtemperature in these tissues. Heat penetration is illustrated by thewave emanating from a source such as a heating pad through the crosssection of the cervical spine and associated tissues.

When the peripheral area heated is the cervical spinal area the heatingelement or heating source 202 can be incorporated into a wearable deviceto that can operatively apply heat to the cervical spinal area. Forexample, the heating source 202 can be incorporated into a wearablepillow. Optionally, the heating source, and portions of the pillow, canbe contoured to portions of the cervical anatomy of the subject toprovide good thermal contact between the heating source and the skin ofthe subject. The pillow also optionally provides overlying thermalinsulation at the site of heating.

Therefore, an effective strategy to control AVAs is to apply localizedheating to the skin in an area peripheral to both the brain and to theglabrous skin containing AVAs having parasympathetic thermal innervationthat controls AVA vasoconstriction. The heated area can be small so asto limit the total heat transfer to the body, avoiding causing asignificant increase in the total energy of the body and a concomitantrise in core temperature. Areas other than the cervical and lumbar spinecan also be heated resulting in vasodilation of AVAs. Increased bloodflow through the AVAs can be readily measured using, for example,Doppler ultrasound techniques. Thus, areas peripheral to the preoptichypothalamus that when heated cause increased blood flow through theAVAs can be readily determined.

A period of thermal stimulation on the skin surface is used to allowsufficient time for heat to diffuse inwardly to reach a depth at whichthe thermal receptors are located interior or proximal to the spine. Thestimulation signal to cause AVA vasodilation may also depend on themagnitude of the spatial temperature gradient from the surface of theskin inward and/or on the temporal gradient causing a rise intemperature. A stimulating signal may be a combination of thetemperature and temperature gradient at the stimulation site.

The heating process is conducted in a manner wherein the temperature ofthe target tissue is increased sufficiently to cause the relaxation ofvasoconstricted AVAs. The amount and method of heating can be sufficientto cause a rise in the target tissue to at least 39° C. In otherembodiments, to at least 40° C. In other embodiments, to at least 41° C.In other embodiments, to at least 42° C. In other embodiments, to atleast 43° C. In all embodiments, the temperature of the target tissuedoes not exceed a safety threshold above which thermally induced injuryoccurs. For most tissues, this threshold temperature is 43° C.

Therefore, the level of thermal stimulation can be above a threshold forcausing AVA vasodilation and below a threshold for causing thermalinjury. The level of stimulation may be within the range of temperaturesof 39° C. to 43° C. for 1 minute or more to cause vasodilation,depending on the initial thermal state of the body. For example, thelevel of stimulation may be within the range of temperatures of 39° C.to 43° C. for 5 minutes or more to cause vasodilation, depending on theinitial thermal state of the body and the method and intensity ofheating.

For methods that involve heating the skin surface, a minimal period ofthermal stimulation may be required to allow sufficient time for heat todiffuse inwardly to reach a depth at which the thermal receptors arelocated that provide inputs that control blood flow to the AVAs. Thestimulation signal to cause AVA vasodilation may also be dependent onthe magnitude of the temperature gradient from the surface of the skininward and the time rate of change of temperature.

The heating process has a duration sufficient to cause an initialincrease in vasodilation of AVAs to allow greater blood flow.Optionally, the heating process is maintained until the AVA vasodilationreaches a maximum value, which can be measured, for example, by Dopplervelocimetry.

Optionally, the heating process will be maintained for the entire periodfor which increased blood flow through the AVAs is desired. The heatingprocess can be activated in a time-wise oscillatory manner in which themagnitude of heating is alternatively increased and decreased. Theperiodicity of the increasing and decreasing heating may have a cyclevarying from less than one second to more than ten minutes. Optionally,where periodicity of heating is applied, the period of a single cyclecan be more than one second and less than 10 minutes.

For embodiments wherein a regime of alternatively increasing anddecreasing heating is applied, the relative periods of greater andlesser or no heating may be equal or unequal. Either the period ofgreater heating or the period of lesser or no heating may be larger ifthey are not equal. For all embodiments, the magnitude of heating can beincreased and decreased at least once, and in some embodiments, morethan one time. For all embodiments the rate of increase of heating andthe rate of decrease of heating may or may not be equal, and both may ormay not be linear. For embodiments for which the heating is not constantfor its duration, the rates and time-wise patterns of increasing anddecreasing magnitudes of heating may be designed and adjusted tomaximize the simulation of the target tissue in the peripheralthermoregulatory control center tissue that regulates the relaxing ofvasoconstricted AVAs. Any desired heating protocol can be implementedusing the computer 224. The heating protocols can be programmed and/ormodified by input 234 from a user.

The described systems and methods can cause the AVAs to becomevasodilated in their base state so that the flow of blood throughglabrous skin can serve as a convective heat transfer medium. If theAVAs are vasoconstricted in a mode that has the objective of conservingthe energy of the body core, a signal consistent with the body rejectingenergy from the core can be used to cause the AVAs to vasodilate. Aprimary vaso-control signal to the AVAs originates in the hypothalamusand is based on the temperature of that tissue. For applications withthe objective of cooling the brain for medical purposes, such as intherapeutic hypothermia, warming the hypothalamus to cause AVAvasodilation is counter-productive.

Referring now to FIG. 5, the combined physiological and thermodynamicmechanism of action is illustrated. For example, as shown in 602,vasodilation can be triggered by heating peripheral input sties ofthermoregulatory control 604. The heating can relax the activevasoconstriction of glabrous AVAs 606. The relaxing of vasoconstriction606 leads to increased perfusion of blood in glabrous skin 608. Theincreased perfusion of blood leads to increased skin temperature in theabsence of surface cooling 610. Thus, the system 200 shown in FIG. 1 canoptionally be used to increase glabrous skin temperature. In thisexample, additional heating or cooling of the glabrous skin is optional.

A method is therefore provided for heating the glabrous skin of amammalian subject comprising applying heat to an area of the subjectthat causes vasodilation of AVAs located in the glabrous tissue. Thismethod may be desirable when increasing the temperature of glabrous skinis desirable, such as, for example, when the subject's hands, feet orface is cold. To implement this method, a system can be used thatcomprises a heating element applied to an area of the subject thatcauses vasodilation of AVAs located in the glabrous tissue. For example,such a system can include a heating element configured for heating theskin or tissues of the cervical spinal or lumbar spinal region.

In other examples, the described systems can be used to heat or cool asubject's core temperature. Referring again to FIG. 1, the system 200can comprise a glabrous skin cooler or heater device 204. For coolingoperation, the device 204 can receive chilled or cooled fluid or gastrough a conduit 208. A pump 210 can actively pump the cooled fluid orgas into and through the device 204. The movement of cooled fluid or gasthrough the device cools the device. A refrigeration device 206, such asa thermoelectric refrigerator, can be used to cool the fluid or gas thatis circulated through the device 204 and conduit 208. The pump 210 andrefrigeration device can both be in operative communication with thecomputer 224 such that the temperature of the device and coolingprotocol of the device can be controlled by the computer and throughuser input 234. If heating of the glabrous skin is desired the device204 can provide heating as an alternative to cooling. The device canapply heat to the glabrous skin and underlying tissues using any of themechanisms described above in relation the heating element 202.

In addition, the system can comprise a temperature sensor 220 positionedto detect the temperature of the device 204 or to detect the temperatureof the glabrous skin in proximity to the device 204. This temperatureinformation can be communicated to the computer 224 where it can beprocessed to determine desired cooling or heating characteristics of thedevice 204 on the glabrous skin.

Optionally, the system 200 further comprises a vacuum 214. The vacuum214 is in operative communication with the device 204 by way of thevacuum line 212. The vacuum can be used to exert negative pressure onthe glabrous skin on which the device 204 is cooling or heating. Thenegative pressure can be used to enhance the dilatation of AVAs in thesubject's glabrous skin. As shown in the system 200, the vacuum andtherefore the negative pressure exerted on the glabrous skin can becontrolled by the computer 224. Specifically, the vacuum is in operativecommunication with the computer 224 by way of a vacuum module 242. Inaddition, the device 204 can be equipped with a pressure sensor 222 thatis in operative communication with the computer 224 by way of a pressuresensing module 240. In this way, the computer 224 may process pressureinformation and temperature information and this information may be usedto adjust factors affecting the operation of the device 204 such as thetemperature or temporal characteristics of the cooling fluid or gascirculated through the device 204 or the negative pressure or temporalcharacteristics thereof.

The system 200, when used with the cooling or heating device 204 can beused to alter the core temperature of a subject's body. In this regard,a temperature sensor 218 can by optionally positioned to take or tomonitor the central temperature of the subject. The temperature sensor218 can be positioned in suitable way for obtaining one or more centraltemperature reading from a subject. For example, the temperature sensorcan be optionally placed in the subject's ear canal, oral cavity orrectum. The temperature sensor can also be optionally paced on theforehead or axillary region of a subject.

Without limiting any specific embodiment to any particular mechanism ofaction, vasodilating and/or enlarging AVAs by heating using the heatingelement 202 causes diversion of a large fraction of cardiac output tothe skin. The skin mediates heat exchange between blood flowing throughthe AVAs and the environment, which heat may then be convected via thecirculation of blood to (for heating) or from (for cooling) the bodythermal core.

The enhanced flow of blood through vasodilated AVAs therefore providesan opportunity to cause an increased flow of energy between the bodysurface and body core by applying heating or cooling to the glabrousskin surface, thereby heating or cooling blood perfused through the AVAsthat will then circulate back to the core at a temperature that willinduce heating or cooling of the core tissues.

Referring again to FIG. 5, a subject's core temperature can optionallybe cooled 612. The steps of cooling the subject's core temperatureinclude cooling the glabrous skin 614. Such cooling can be accomplishedas described above using the device 204. Cooling of the glabrous skin614 causes diffusion of heat from deep skin structures to the surface616. In addition, the method can comprise increasing the perfusion ofblood in the glabrous skin as shown in steps 602-608.

The combination of the increased perfusion of blood in the glabrous skin608 and diffusion of heat from deep skin structures to the surface 616results in convective cooling of blood flowing through AVAs in theglabrous skin 618. The cooled blood is circulated from the peripheralAVAs to the body core with minimal heat exchange 620. This results inconvective warming of the blood in the body core to lower the coretemperature 622. A peripheral thermal stimulation may be required to bemaintained past the initial time at which vasodilation starts, up to theentire period during which cooling may be applied to glabrous skin withvasodilated AVAs to produce a progressively increasing state oftherapeutic hypothermia. Optionally, surface cooling is provided to anarea of glabrous skin and simultaneous warming to a small area of skinrich in thermal parasympathetic innervations that controls AVA bloodflow.

In the described systems and methods, cooling may be produced by theapplication of one or more pre-chilled gel packs having a mass andinitial temperature sized to produce a desired drop in body thermal coretemperature, or, alternatively, warming may be produced by applicationof one or more pre-warmed gel packs to produce a required increase inbody thermal core temperature. The pre-chilled and pre-warmed gel packsmay be reusable or disposable following use.

Cooling may optionally be produced by the mixing of chemical elementscontained within a flexible package that undergo an endothermic processwhen mixed thereby reducing the temperature of the mixture. The mixturecomponents may be prepackaged in a single pack with interior barriersthat separate the chemical components until the time when the cooling isto be produced, whereupon the barriers may be ruptured to enable themixing of components with an endothermic effect.

Also referring to FIG. 5, a subject's core temperature can optionally beheated 624. The steps of heating the subject's core temperature includeheating the glabrous skin 626. Such heating can be accomplished asdescribed above using the device 204. Heating of the glabrous skin 626causes diffusion of heat away from the skin surface and towards the deepskin structures 628. In addition, the method can comprise increasing theperfusion of blood in the glabrous skin as shown in steps 602-608. Thecombination of the increased perfusion of blood in the glabrous skin 608and diffusion of heat towards the deep skin structures results inconvective warming of blood flowing through AVAs in the glabrous skin630. The warmed blood is circulated from the peripheral AVAs to the bodycore with minimal heat exchange 632. This results in convective coolingof the blood in the body core to raise the core temperature 634.Optionally, surface warming is provided to an area of glabrous skin andsimultaneous warming to a small area of skin rich in thermalparasympathetic innervations that controls AVA blood flow.

Warming may be produced by mixing chemical elements that undergo anexothermic process causing the temperature of the mixture to rise. Insome embodiments, warming may be generated by exposing a sealed packageof chemicals to oxygen or air by rupturing an impermeable sealing coverresulting in a sustained increase in temperature of the pack. Thechemical mixing packs that operate by rupturing a membrane or barrier orcover are disposable after a single use.

Pre-chilled and pre-warmed gel packs and endothermic and exothermicchemical mixing packs may all be flexible allowing for conformation ofthe pack to the shape of the glabrous skin surface, thereby ensuringbetter thermal contact than if the cooling or warming substrate isrigid.

In some embodiments the chilled or warmed packs may be locatedperipherally to the glabrous skin where they cool or warm a liquid thatis circulated under the action of a pump to a flexible bladderpositioned in contact with glabrous skin.

In some embodiments, a warming or cooling pack applied to glabrous skinmay be equipped with one or more attachment straps to aid in maintainingeffective thermal contact between the pack and glabrous skin. Theseembodiments may be particularly useful under conditions in which asubject is unable to actively participate in ensuring that a best levelof heat transfer occurs between the pack and skin, such as when thesubject is not aware of the treatment process or is unconscious.

Referring now to FIGS. 2A and 2B, an example system 300 is shown forcooling core body temperature. As described with relation to FIG. 1, theexample system comprises a computer 224 and a heating element 202. Theheating element can be used to heat subject tissue to lead to dilationof AVAs in the subject's glabrous skin. A temperature sensor 216, alsodescribed, above can detect the temperature of the skin and/or tissue inproximity to the heating element 202. As the temperature sensor 216 isin operative communication with the computer 224 temperature readingsfrom the temperature sensor can be used to provide a desired level ofheating from the heating element 202.

The system 300 further comprises a heat exchanger in communication withthe conduit 208 comprising the cooling fluid or gas. The heat exchangercan comprise a compressor 306 and a source of refrigerant 302, such asR12. The heat exchanger can further comprise a temperature sensor 308 tosense the temperature of refrigerant prior to the conduit 208 and asecond temperature sensor 310 subsequent to the conduit. Refrigerant canbe circulated through the tube 304 to cool fluid in the conduit 208.

The conduit 208 can hold cooled fluid or gas that can be pumped into andthrough a cooling sleeve 301. The cooling sleeve 301 can be optionallyplaced over the glabrous skin of the hand, foot, or face. FIG. 2B showsa cross section of the sleeve across the line 2B-2B. Two additionaltemperature sensors can be positioned to monitor the temperature of thefluid or gas in the conduit. A first temperature sensor 314 candetect/monitor the temperature of fluid or gas entering the sleeve. Asecond temperature sensor 312 can detect/monitor the temperature offluid or gas leaving the sleeve.

Each temperature sensor 308, 310, 312 and 314 may be in operativecommunication with the computer 224 through a temperature sensor module244. In addition, the compressor 306 and the pump 308 are also inoperative communication with the computer 224 through a compressor 316and pump 240 module respectively. Information collected from thetemperature sensors and the flux through the heat exchanger can be usedto cool the fluid or gas in the conduit 208, and thus the sleeve 301 toa desired temperature.

As shown in the systems 200 and 300, the methods described herein can beimplemented via a general-purpose computing device in the form of acomputer 224. The components of the computer 224 can include, but arenot limited to, one or more processors or processing units 226, a systemmemory 228, and a system bus that couples various system componentsincluding the processor 226 to the system memory 228.

The system bus may represent one or more of several possible types ofbus structures, including a memory bus or memory controller, aperipheral bus, an accelerated graphics port, and a processor or localbus using any of a variety of bus architectures. By way of example, sucharchitectures can include an Industry Standard Architecture (ISA) bus, aMicro Channel Architecture (MCA) bus, an Enhanced ISA (EISA) bus, aVideo Electronics Standards Association (VESA) local bus, and aPeripheral Component Interconnects (PCI) bus also known as a Mezzaninebus. The bus, and all buses specified in this description, can also beimplemented over a wired or wireless network connection and each of thesubsystems, including the processor 226, a mass storage device 230, anoperating system, application software, data, a network adapter, systemmemory, an Input/Output Interface, a display adapter, a display device,and a human machine interface, can be contained within one or moreremote computing devices at physically separate locations, connectedthrough buses of this form, in effect implementing a fully distributedsystem.

The computer 224 typically includes a variety of computer readablemedia. Such media can be any available media that is accessible by thecomputer 224 and includes both volatile and non-volatile media,removable and non-removable media. The system memory 228 includescomputer readable media in the form of volatile memory, such as randomaccess memory (RAM), and/or non-volatile memory, such as read onlymemory (ROM). The system memory 228 typically contains data such as dataand and/or program modules such as operating system and applicationsoftware that are immediately accessible to and/or are presentlyoperated on by the processing unit 226. The computer 226 may alsoinclude other removable/non-removable, volatile/non-volatile computerstorage media. A mass storage device 230 can be a hard disk, a removablemagnetic disk, a removable optical disk, magnetic cassettes or othermagnetic storage devices, flash memory cards, CD-ROM, digital versatiledisks (DVD) or other optical storage, random access memories (RAM), readonly memories (ROM), electrically erasable programmable read-only memory(EEPROM), and the like.

Any number of program modules can be stored on the mass storage device230, including by way of example, an operating system and applicationsoftware. Each of the operating system and application software (or somecombination thereof) may include elements of the programming and theapplication software. Data can also be stored on the mass storagedevice. Data can be stored in any of one or more databases known in theart. Examples of such databases include, DB2®, Microsoft® Access,Microsoft® SQL Server, Oracle®, mySQL, PostgreSQL, and the like. Thedatabases can be centralized or distributed across multiple systems.

A user can enter commands and information into the computer 224 via aninput device. Examples of such input devices include, but are notlimited to, a keyboard, pointing device (e.g., a “mouse”), a microphone,a joystick, a serial port, a scanner, and the like. These and otherinput devices can be connected to the processing unit 226 via a humanmachine interface that is coupled to the system bus, but may beconnected by other interface and bus structures, such as a parallelport, game port, or a universal serial bus (USB).

The computer 224 can operate in a networked environment using logicalconnections to one or more remote computing devices. By way of example,a remote computing device can be a personal computer, portable computer,a server, a router, a network computer, a peer device or other commonnetwork node, and so on. Logical connections between the computer 223and a remote computing device can be made via a local area network (LAN)and a general wide area network (WAN). Such network connections can bethrough a network adapter. A network adapter can be implemented in bothwired and wireless environments. Such networking environments arecommonplace in offices, enterprise-wide computer networks, intranets,and the Internet.

An implementation of application software may be stored on ortransmitted across some form of computer readable media. Computerreadable media can be any available media that can be accessed by acomputer. By way of example, and not limitation, computer readable mediamay comprise “computer storage media” and “communications media.”“Computer storage media” include volatile and non-volatile, removableand non-removable media implemented in any method or technology forstorage of information such as computer readable instructions, datastructures, program modules, or other data.

Computer storage media includes, but is not limited to, RAM, ROM,EEPROM, flash memory or other memory technology, CD-ROM, digitalversatile disks (DVD) or other optical storage, magnetic cassettes,magnetic tape, magnetic disk storage or other magnetic storage devices,or any other medium which can be used to store the desired informationand which can be accessed by a computer. An implementation of thedisclosed method may be stored on or transmitted across some form ofcomputer readable media.

The processing of the disclosed method can be performed by softwarecomponents. The disclosed method may be described in the general contextof computer-executable instructions, such as program modules, beingexecuted by one or more computers or other devices. Generally, programmodules include computer code, routines, programs, objects, components,data structures, etc. that perform particular tasks or implementparticular abstract data types. The disclosed method may also bepracticed in grid-based and distributed computing environments wheretasks are performed by remote processing devices that are linked througha communications network. In a distributed computing environment,program modules may be located in both local and remote computer storagemedia including memory storage devices.

Although, the embodiments described above in relation to the system 200and 300 can be used to cool or heat core temperature in accordance withaspects of the invention, it should be noted that features of thesesystems, including the computer 224, are optional. For example, a systemfor cooling core body temperature can include a heating element forheating skin or tissue of a subject that results in dilation of AVAs inglabrous skin. The system can further comprise a cooling device thatprovides a cooling stimulus to glabrous skin of a subject. Such acooling device is optionally a cooled container of fluid, a cooled gelpack, an ice cube, or a cooled source of gas. Similarly, a device usedto heat core temperature can comprise a heating element for heating skinor tissue of a subject that results in dilation of AVAs in glabrousskin. The system for heating can further comprise a heating device forproviding a heating stimulus to glabrous skin of a subject.

Referring now to FIG. 4 an example system is illustrated in which acontroller is applied to coordinate the magnitudes of spine heating (Ts)and palmar (Th) heating or cooling and plantar (Tf) heating or coolingas functions of temperature inputs for the core (Tc), spine (Ts) andpalmar (Th) and plantar (Tf) skin surfaces. A controller algorithmprovides safety to the user and optimum thermal performance forapplications in which the core temperature of the user is beingmanipulated.

FIGS. 6A and B show example devices 404 and 406 for cooling or heatingthe palmar or plantar glabrous skin respectively. Such example devicescan optionally used in the system 200 and 300 as system element 204.Optionally, 404 and 406 are used for cooling and a conduit 208 directsflow of cooled fluid or gas through the devices to provide a coolingstimulus to the palmar or plantar glabrous skin.

FIG. 6A illustrates methods and devices for heating or cooling thesurface of glabrous palmar skin and ventral aspect of the fingers of thehand that contain arteriovenous anastomosis vascular structures caninclude establishing a contact area with a flexible hot or cold sourcebladder at a specified temperature through which flows a controlledtemperature fluid via inlet and outlet ports thereby providing a thermalmechanism of adding or removing energy to or from the glabrous skin,according to a specific embodiment of the disclosure.

FIG. 6B illustrates methods and devices for heating or cooling thesurface of glabrous plantar skin and ventral aspect of the toes of thefoot that contain arteriovenous anastomosis vascular structures byestablishing a contract area with a flexible hot or cold source bladderat a specified temperature through which flows a controlled temperaturefluid via inlet and outlet ports thereby providing a thermal mechanismof adding or removing energy to or from the glabrous skin, according toa specific example embodiment of the disclosure.

As described with regard to the systems 200 and 300, according to someembodiments, the disclosed systems and methods may comprise applying anegative pressure to at least a portion of a subject's skin. Forexample, negative pressure may be applied to glabrous skin on the hands,feet and/or face. In some embodiments, a surface vacuum system may bemaintained at a predetermined negative pressure until the warming orcooling is achieved, i.e. till the body core of a subject reaches thedesired temperature.

Optionally, a chilled or warmed pack may be located peripherally to avacuum chamber and glabrous skin where they cool or warm a liquid thatis circulated under the action of a pump to a flexible bladderpositioned in the interior of the vacuum chamber in contact withglabrous skin.

The negative pressure may optionally be up to about 25 mm Hg, up toabout 50 mm Hg, up to about 75 mm Hg, and/or up to about 100 mm Hg. Insome embodiments, the devices of the disclosure may produce negativepressure by a portable surface vacuum system that comprises a means formanual evacuation, for example, by a manual bulb pumping device or amanual lineal pumping device or a manual rotary pumping device or amanual hinged pumping device or a bellows pumping device or aself-contained battery operated vacuum pump.

A manual vacuum generating system may be operated by application of themotion of a hand, of both hands, of a foot, of both feet, of acombination of hands and feet, or by application of relative motion ofother body members. The manual vacuum generating system may be operatedby a single person or by the cooperation of multiple people.

A portable surface vacuum system comprises a vacuum pump that may beoperably attached to an impermeable cover designed to cover only theglabrous skin surface which is being cooled or heated. An impermeablecover may comprise a suction port that is attached to a vacuum pump anda peripheral seal operable to seal in vacuum generated by the vacuumpump onto a glabrous skin surface of the body of the mammal. A surfacevacuum system may also comprise a heating or a cooling means fordelivering heat or cold to a glabrous surface.

Optionally, a portable surface vacuum system is used to apply negativepressure without insertion of a body appendage into a non-portableand/or rigid vacuum chamber. In these embodiments, the outer surface ofthe vacuum confining volume (i.e. vacuum chamber or negative pressurechamber) may be made with an impermeable flexible material. A cooling orwarming pack may be placed against glabrous skin at a site of treatmentprior to being covered with such an impermeable flexible material. Theimpermeable flexible material may be sealed against the glabrous skinaround its periphery. A port placed in the impermeable flexible materialprovides a connection to a vacuum generating device so that the volumeinterior to the sealed perimeter may be evacuated to desired level ofnegative pressure. When a vacuum is created therein the action ofatmospheric pressure on the outer surface of the impermeable flexiblematerial translates a mechanical force onto a heating pack or a coolingpack placed against the glabrous skin on the interior, increasing thepressure of the pack onto the skin, thereby reducing the thermalresistance between the pack and the skin and producing more effectiveheat transfer between the pack and the skin.

In other embodiments, a portable surface vacuum system of the disclosureallows for application of negative pressure by insertion of a bodyappendage into a portable rigid vacuum chamber. A rigid chamber does notsubstantially change its shape when a vacuum is created on the interior.A rigid chamber incorporates a sealing element at the location where abody appendage is inserted into the chamber so that a seal is createdaround the perimeter of the appendage to support and maintain a negativepressure on the interior of the chamber.

In some embodiments, a rigid chamber of a portable vacuum device of thedisclosure, may have a second opening with a sealing cover having a sizesufficient to permit insertion of a cooling or warming pack and for anoperator to position said pack in contact with the body appendage of thetreatment subject.

The sealing cover may be opened and closed easily and quickly, and inthe closed position it supports the generation of a negative pressure inthe interior of the rigid chamber. The sealing cover may be opened andclosed by pivoting on hinges or by turning screw threads or by looseningand fastening latches. A sealing medium is placed between the matingsurfaces of the cover and the rigid chamber to block the flow of airwhen a negative pressure is generated interior to the rigid chamber. Therigid chamber may have a mechanical vacuum gauge installed to enable anoperator to monitor the state of vacuum.

In some embodiments, the surface vacuum system may cover about 50 mm² orless of glabrous skin. Other embodiments may cover up to about 500 mm²of glabrous skin. In some applications multiple areas of glabrous skinmay be treated simultaneously so that the total treatment area isadditive of the individual areas. The actual treatment area may varywidely depending on the area of the body having glabrous skin that isselected for the process, the number of sites, and the overall size ofthe subject.

Referring now to FIGS. 7-14, example devices for use with the describedsystems and methods are provided. FIG. 7 illustrates a cross sectionalview of a portable negative pressure device comprising a warming orcooling pack 5 in contact with the surface of glabrous skin 4. Aflexible impermeable cover 1 is positioned over the application areawith a seal 2 around the perimeter. A negative pressure 3 interior tothe cover is formed and applied to the glabrous skin. A gauge 7 can beused to monitor the level of negative pressure, and a source of pumping8 (vacuum) with a connection 6 to the interior of the impermeable coveris used to generate the negative pressure therein. The device shown inFIG. 7 can, for example, be used as the glabrous skin cooling device 204of systems 200 and 300.

FIG. 8 illustrates a negative pressure device including a portablesurface vacuum device having a rigid vessel 20 into which an appendageof a body 23 may be inserted with a pressure seal 24 circumferentiallyon the skin at the point of insertion. A warming or cooling pack 21 ispositioned in contact with the surface of glabrous skin under conditionsof negative pressure on the interior of the vessel. A source is providedfor generating a negative pressure 27 inside the vessel 20 and connected26 to the vessel interior and a gauge 25 is used for monitoring thedegree of negative pressure. The device shown in FIG. 8 can, forexample, be used as the glabrous skin cooling device 204 of systems 200and 300.

FIG. 9 illustrates a portable negative pressure device including a rigidvessel/chamber 31 into which an appendage of a body may be inserted witha pressure seal circumferentially on the skin at the point of insertion.A second opening 33 through which a warming or cooling pack may beinserted can be in contact with the surface of glabrous skin underconditions of negative pressure on the interior of the vessel. Thesecond opening can be opened and closed by rotating a removable element32 having male screw threads 34 that match female threads 35 on anopening in the rigid vessel. A sealing substance such as Teflon tape 36is optionally applied to the screw threads to provide a seal between thesecond removable element and the rigid container when the second elementis attached so as to contain the negative pressure interior to the rigidvessel. The removable element has an appendage 37 that can be grasped torotate the element for installing or removing the element from the rigidvessel of the portable surface vacuum chamber. The device shown in FIG.9 can, for example, be used as the glabrous skin cooling device 204 ofsystems 200 and 300.

FIG. 10 illustrates a negative pressure device including a portablesurface vacuum chamber having a rigid vessel 41 into which an appendageof a body may be inserted with a pressure seal circumferentially on theskin at the point of insertion. The device further comprises a secondopening 44 through which a warming or cooling pack may be inserted to bein contact with the surface of glabrous skin under conditions ofnegative pressure on the interior of the vessel. The second opening canbe opened and closed by pivoting a second element 42 attached by one ofmore hinges 43 to a portion of the perimeter of the opening in the rigidvessel. One or more latches 46 mounted on a pivot 49 and matching pins47 or other locking devices are used to secure the second element in asealed position against the second opening in the rigid vessel. Asealing substance such as Teflon tape is optionally applied to themating surfaces 45 of the rigid vessel and/or second element to providea seal between the second hinged element and the rigid container whenthe second element is rotated to a closed position against the rigidvessel so as to contain the negative pressure interior to the rigidvessel. A handle 48 is provided to open and close the second element.The device shown in FIG. 10 can, for example, be used as the glabrousskin cooling device 204 of systems 200 and 300.

FIG. 11 illustrates a negative pressure device including a portablevacuum chamber having a rigid vessel 61 into which an appendage of abody may be inserted with a pressure seal circumferentially on the skinat the point of insertion. The device includes a second opening 63through which a warming or cooling pack may be inserted to be in contactwith the surface of glabrous skin under conditions of negative pressureon the interior of the vessel. The second opening can be opened andclosed by removal a second element 62 that is shaped to match theopening in the rigid vessel. One or more latches 65 is mounted on apivot 66 and matching pins 67 or other locking devices are used tosecure the second element in a sealed position against the secondopening in the rigid vessel. A sealing substance such as Teflon tape isoptionally applied to the mating surfaces 64 of the rigid vessel and/orsecond element to provide a seal between the second element and therigid container when the second element is positioned to a closedposition against the rigid vessel so as to contain the negative pressureinterior to the rigid vessel. The device shown in FIG. 11 can, forexample, be used as the glabrous skin cooling device 204 of systems 200and 300.

FIG. 12 illustrates a negative pressure device vacuum generating device.The device includes an impermeable cover 91 operably attached 86 to thevacuum generating device 87 to produce a negative pressure on theinterior 88 of the impermeable cover. The impermeable cover is operableto cover a glabrous skin surface 81. The impermeable cover has a sealingmeans 83 to seal a perimeter area of the glabrous skin. The impermeablecover encloses a flexible cooling or warming pack 84 in its interior andpositioned against glabrous skin so that it may exchange heat with theskin. The impermeable cover is optionally flexible so that the combinedactions of the higher exterior pressure 89 and the lower interiorpressure 85 when applied across the surface area 82 of the impermeablecover results in a mechanical force 90 applied onto the flexible coolingor heating pack to force it against the glabrous skin providing areduced thermal contact resistance at the interface and improved heattransfer between the pack and the glabrous skin. The device shown inFIG. 12 can, for example, be used as the glabrous skin cooling device204 of systems 200 and 300.

FIG. 13 illustrates a negative pressure volume containment device 100which may be applied to seal a defined area of glabrous skin and intowhich may be placed a cooling or warming pack 103 to transfer heat fromor to the skin. A peripheral seal 102 is formed around the bodyappendage 101 containing glabrous skin. A pressure monitoring device 104is used to continuously measure the pressure within the negativepressure device. The device also includes a connection 105 to a vacuumgenerating source 106 which is operable in the absence of external powersources. Operation may be by manual means such as manual compression ofa confined volume (a bellows or a bulb or other flexible compressiondevice 110), a linear pumping motion 108, a rotary pumping motion 109,or by a powered means in which a portable self-contained energy source107 such as a battery drives a vacuum pump. The device shown in FIG. 13can, for example, be used as the glabrous skin cooling device 204 ofsystems 200 and 300.

FIG. 14 illustrates a flexible cooling or warming pack 120 that may beinserted into the interior of a negative pressure volume as shown in theprior figures to contact and conform to the topology of glabrous skin ofa mammal while transferring heat to or from the skin. The pack may bebrought to a desired treatment temperature by pre-cooling orpre-heating, by mixing contained chemical components previouslyseparated by barriers that may be ruptured at the time of treatment toallow an endothermic or exothermic mixing process, or by exposingcontained chemical components to air causing an exothermic reactionafter the pack is removed from an initially sealed container, accordingto a specific example of the disclosure.

As described throughout, control of blood flow through the arteriovenousanastomoses of the skin is critical to thermoregulatory function. Theability to manipulate blood flow through the AVAs, especially from anincipient state of vasoconstriction, holds important consequences formedical applications that involve the modulation of core bodytemperature and for alleviating issues of personal thermal discomfort.

Described herein are methods, processes, systems and devices foraccomplishing on demand increases in the flow of blood through the AVAsand thereby the ability to raise or lower the body core temperature. Insome embodiments, arteriovenous anastomoses (AVAs), may be dilatedand/or distended. Without limiting any specific embodiment to anyparticular mechanism of action, dilating and/or distending AVAs maycause diversion of a large fraction of cardiac output to the skin. Theskin may mediate heat exchange with the environment which may then beconvected to the body thermal core. In some embodiments, the rate ofcore temperature change may be ten times faster than possible usingexisting conventional methods and devices in the absence of AVAvasodilation and/or distention enhancements.

The described systems and methods can be used to cool and/or heat thecore temperature of a mammal that may or may not initially bevasoconstricted. In conjunction with thermal stimulation of peripheralsites of thermoregulatory control to produce greater blood perfusion toglabrous skin, the surface of glabrous skin may be heated or cooled torespectively add or remove heat from blood circulating from the bodycore. The disclosed methods and devices are capable of increasing ondemand the convective flow of heat between the skin surface and the bodycore via the circulation of blood. The methods and devices may beapplied to lower the body core temperature from a normothermic state toproduce a state of hypothermia, and from a hyperthermic state toward anormothermic state, and to increase the body core temperature from ahypothermic state toward a normothermic state, and from a normothermicstate to a hyperthermic state. An example application of the latterprocess could be instances where it is desirable to create an artificialfebrile state to enhance cancer therapies.

For some embodiments in which the AVAs are initially in at least apartial state of vasoconstriction, the vasoconstriction action of theAVAs is relaxed or reduced at least in part by the method of heatingthermal receptors in the thermoregulatory control center peripheral tothe brain so as to stimulate the requisite input signals to reducevasoconstriction in the AVAs. The result of increased AVA vasodilationis greatly decreased flow resistance of the AVAs such that there is adiversion of a larger fraction of the cardiac output to the AVAs.

As a consequence of the increased blood flow through the AVAs, theglabrous skin will be warmed by the greater convective heat transferwith blood flowing from the warmer body core. The described systems andmethods can implement various specific devices and processes for heatingto thermally stimulate peripheral thermoregulatory control tissue thatcause the process of warming glabrous skin via increased convective heatexchange with warm core blood.

As a further consequence of the increased blood flow through the AVAs,the glabrous skin can be used as a heat transfer medium between heatingor cooling sources applied to its surface and blood flowing through theAVAs. The process creates the opportunity to adjust the temperature of afraction of the cardiac output which is circulated back to the bodycore, with minimal heat exchange in the intermediate larger diameter andhigher velocity vessels, until it equilibrates thermally with the totalblood volume and tissues of the body core, thereby providing a directtransport link to externally modulate the body core temperature.

The described systems and methods can be used to rapidly increase ordecrease the core body temperature of a mammalian body for therapeuticand other uses. For example, induction of hypothermia providesprotection to the brain from ischemic events in subjects that may havesuffered impairments such as cardiopulmonary arrest, ischemic stroke,subarachnoid hemorrhage, hepatic encephalopathy, perinatal asphyxia,infantile viral encephalitis, or an acute traumatic brain injury.

The described systems and methods may be used to cool the body of a userin response to a hyperthermia-inducing activity or event. Somenon-limiting examples of hyperthermia-inducing activities includeendurance-limited activities such as athletic performance, and/orworking in an environment of high heat (mining industry, constructionindustry, forestry industry, metals processing industry), and/orexposure to an environment of high heat stress, and/or militaryoperations. The described systems and methods may also be used toameliorate or eliminate the effects of warming of the body temperatureto mortally dangerous temperatures higher than the normal operatingrange.

The described systems and methods may be used to warm the body of ahuman user in response to a hypothermia-inducing activity or event. Somenon-limiting examples of hypothermia-inducing activities include workingin extremely cold environments, and/or extended exposure to a very coldenvironment, particularly in the absence of a significant level ofphysical activity, and/or prolonged exposure to water, and/or prolongedathletic activities in cold/water-based environments, and/or beingseated in a vehicle under cold conditions. The described systems andmethods may be used to ameliorate or eliminate the effects of excessivecooling of the body core temperature that may lead to injury and/ordeath.

The described systems and methods may safely extend the performanceenvelope for any of the foregoing types of activities and/or safelyextend the period of exposure to the extreme temperature by adjustingthe temperature of the body core. In some embodiments, the user maycontinue to engage in the activity or continue to be exposed to theextreme temperature as mobility of the user is not hindered.

The described systems and methods may be used to induce a state of mildhypothermia of up to 2° C. without any techniques that are invasive tothe skin surface and/or that require sterile conditions and/or thatrequire access to central electrical power. In some embodiments thedevice or method of the disclosure can be practiced by personnel with alevel of training commensurate with EMS medical personnel and in fieldconditions without access to central electrical power.

The described systems and methods may be used to induce therapeutichypothermia for subjects or people at risk of ischemic injury. Forexample, localized heating may be applied to a peripheral site ofthermoregulatory control to cause relaxation of arteriovenousanastomosis vasoconstriction to produce greater blood perfusion ofglabrous skin that can then be locally cooled to enhance convective heattransfer in the skin to produce rapid cooling of the body thermal coreto a state of therapeutic hypothermia. This may be used to providetreatment or neuroprotection for medical cases such as cardiac arrest,stroke, traumatic brain injury, vasculature surgery, neonatal braininjury and combinations thereof.

Optionally, the systems, devices and methods can be operated orperformed without external AC electrical power sources. It may bepossible to attach the system or a portion of the systems described to astationary electrical power source operating an electrically drivenvacuum pump for applications in which the device is positioned withinphysical access of such power sources.

Optionally, the described systems and devices are portable. In someembodiments, a device of the disclosure may be light-weight. Portabilityand/or the ability to operate without an external AC electrical powersource and/or light-weight may provide operational functionality in someapplications. For example, portability and/or light-weight provide anadvantage for use in an EMS vehicle, in a medical helicopter, in acommercial airliner, in a military operational vehicle, at an industrialwork site, a sports playing field, and a remote activity venue. Theportability and light-weight may make the device desirable to carry onspace craft or an aircraft to provide immediate life saving treatment toa subject who suffers an ischemic event. Optionally, the systems anddevice may be sufficiently compact to be placed and carried in a firstaid kit.

In some embodiments, use of a surface vacuum system to apply negativepressure to a portion of a glabrous skin surface removes the necessityof inserting an appendage comprising glabrous skin into a rigid vacuumcontainer.

The systems and devices of the disclosure may be completely portable andrequire no external AC electrical power sources rendering them usable incritical medical care situations such at the site of an injury or roadaccident, or while being carried on an ambulance or helicopter toprovide important rapid cooling therapy for victims of cardiac arrest,stroke, traumatic head injury, or neonatal brain injuries or impairmentto provide protection from possible ischemic injury. The presentdisclosure, in some embodiments, relates to portable heating or coolingdevices, methods of inducing flow of blood to the AVAs when it isinitially not active, and methods to regulate and/or adjust and/ormodify the body core temperature while allowing mobility, e.g. completemobility, for the user.

Optionally, the surface of glabrous skin may be heated or cooled so asto modulate the body core temperature without adversely affectingenhanced AVA blood flow and for implementation in a wide diversity ofvenues and circumstances where the medical benefits of adjusting thebody core temperature may be desired. Of note, the latter venues andcircumstance may include producing a state of mild hypothermia shortlyfollowing an ischemia producing event in a location remote from amedical care facility.

The systems or devices of can be optionally attached to a stationaryelectrical power source operating an electrically driven heat transferfluid pump and refrigeration system for applications in which the deviceis positioned within physical access of such power sources. In someembodiments, a device of the disclosure may be portable.

The present disclosure provides methods and devices that can elicitblood perfusion to the AVAs in glabrous skin via focal thermalstimulation to key sites of peripheral thermoregulatory control. Thermalstimulation to sites of peripheral thermoregulatory control havingparasympathetic innervation sends signals to AVAs in glabrous skin thatcause vasoconstriction to relax, producing increased blood flow toglabrous skin. One outcome of this stimulation is that in the absence oflocal heating or cooling, the glabrous skin will be warmed from theformer state of vasoconstriction. This outcome can be used to benefit ininstances wherein warming of the hands and/or feet will cause anincrease in the state of thermal comfort.

One application of this process is to incorporate the thermalstimulation into the upper seat back of a vehicle whereby the cervicalspine can be heated in order to enhance the comfort of occupants whenthe environmental temperature is low enough to cause discomfort.Additional applications include maintaining warmth of the palmar andplantar skin for situations in which is a person is exposed to a coldenvironment in combination with a low level of physical activity over anextended period of time, such watching an athletic event, waiting in ahunting blind, recording observations of the heavens, and innumerableother situations. The invention can be used in a residential setting forany conditions in which the hands and feet become uncomfortably cold andduring any time of day or night. Medical applications may include thewarming of patients who are uncomfortably cold. It may be combined withwarming of the glabrous skin surfaces to add heat to blood circulatedthrough the AVAs so as to circulate heat to the body core to warm itfrom a state of hypothermia as may be required.

Thermal stimulation may be induced by various means, including directcontact of the skin with a heated surface, directing a flow of warm aironto the stimulation site, and/or applying surface and/or penetratingelectromagnetic energy at controlled wavelengths and intensity.Different means of thermal stimulation can alter the process time todiminish vasoconstriction of AVAs in order to match requirements forachieving comfort or medical benefit. The intensity of thermalstimulation may be regulated via a feedback control loop in order toensure safety against causing thermal injury during stimulation and toprovide optimal control of AVA vasodilation.

The physiological mechanisms that govern heat transfer between glabrousskin and the body core via convective blood flow through the AVAs asenhanced by application of spinal heating to relax vasoconstriction ofAVAs and by application of negative pressure to glabrous skin to distendAVAs were evaluated.

Example 1

The application of negative pressure to glabrous skin was used to causea significant increase in the flow of blood through the AVA vascularstructure and the associated retia venosa. A laser Doppler flow probewas used to measure the change in blood flow in glabrous skin as afunction of the magnitude of applied negative pressure.

A human hand was placed into a sealed rigid vacuum chamber on which wasmounted an electronic negative pressure gauge. An optical laser Dopplerflow probe was mounted onto the skin of the most distal pad of themiddle finger to monitor blood flow continuously. The finger was exposedto ambient temperature air with no active cooling or warming applied tothe skin. Control measurements were made with no negative pressureapplied following an initial acclimatization period. The negativepressure was increased to a predetermined level and held for 15 minutes,then returned to zero.

Data from a sample protocol at a negative pressure of approximately 40mm Hg is shown in FIG. 15. FIG. 15 depicts a blood flow plot andillustrates transient variation that is typical of AVA vasoactivity asthe lumen diameter changes with time and thereby alters both flowimpedance and velocity. Several features regarding the mechanistic basisof this physiological phenomenon are reflected in the data. For example,firstly under the action of negative pressure the average bloodperfusion rate increases by approximately 30%, which is important fornegative pressure technology function. Secondly, there is a sharptransient vasoconstriction of the AVAs in conjunction with major changesin the applied negative pressure, regardless of whether the change inpressure is positive or negative. This sympathetic driven behavior is atypical response to a sudden environmental input to the body. Third,after the negative pressure is removed the perfusion rate returns toapproximately the level prior to the application of negative pressure.This behavior points to a direct cause and effect relationship betweenthe increase in perfusion and applied negative pressure. Fourth, thereis a large increase in perfusion by a factor of approximately threeduring the initial acclimatization period from an initial native stateof AVA vasoconstriction.

The laser Doppler probe was also used to measure the skin surfacetemperature at the site of the perfusion measurement. FIG. 16illustrates the temperature history during this experiment. At the startof the experiment, initial temperature of the skin was 24° C., which isindicative of a vasoconstricted state as is confirmed by thecorrespondingly low value of AVA perfusion. FIG. 15 shows a steadytransition in blood flow over the first 11 minutes in the absence ofnegative pressure to a vasodilated state. FIG. 16 documents acorresponding rise in the skin temperature by approximately 8° C. to anew equilibrium value as the increased flow of warm blood from the bodycore through the AVAs caused an interior convective source thattranslated to the progressive warming of the skin surface. This datashows the coupling between AVA perfusion level and skin heat transferand temperature.

FIG. 15 further shows the application of negative pressure at 11 minuteswith a commensurate increase in AVA perfusion. A higher perfusion ratetranslates into a greater convection effect between warm blood and theskin tissue, issuing in a further increment in surface temperature. FIG.16 documents the further increment in surface temperature by 2° C. as aresult of the application of negative pressure. The net increase insurface temperature of the skin was 10° C. as a result of the increasein AVA perfusion. The two steps of temperature increments correspond tothe two steps in perfusion increment, demonstrating mechanistic couplingof the two phenomena. The mechanistic action of blood perfusion onconvective heat transfer in the glabrous skin is verified by these data.

Example 2

A series of tests, similar to those described above and shown in FIG.15, were conducted, each at a different value of negative pressure. Theobjective was to determine whether there is a proportional relationshipbetween the magnitude of increase in perfusion and the magnitude of theapplied negative pressure. Results of these experiments are shown inFIG. 17 which illustrates increments in blood perfusion measured bylaser Doppler velocimetry on the most distal pad of the middle fingerwhen exposed to various (graded) negative pressure values at roomtemperature air.

These data document a clear proportional relationship between appliednegative pressure and the resulting increase in AVA perfusion. Themechanistic action of negative pressure on blood perfusion in thesubject technology is verified by these data.

Example 3

The palm surface of the hand was subjected to cooling by contacting itwith a flexible bladder through which chilled water was circulated atthe same time that negative pressure was applied interior to a rigidchamber. A heat flux gauge and thermocouple were affixed to the palm inan area where it contacted the bladder. The protocol consisted of anequilibration period at room temperature, followed sequentially by theapplication of negative pressure, then bladder perfusion with water at17° C., then cessation of negative pressure, reestablishment of negativepressure, and a final cessation of negative pressure.

FIG. 18 shows data from this experiment in which water having atemperature of 23° C. was circulated through a bladder in contact withthe palm of the hand. A significant enhancement in skin heat fluxoccurred (most upper lines of FIG. 18) when negative pressure (mostlower lines of FIG. 18) was applied, which diminished when the negativepressure was removed. The temperature of the skin at the site of heatflux measurement is shown as the least variant plot.

After an eleven (11) minute equilibration period, negative pressure wasincreased to 40 mm Hg (which held the heat flux constant), and at 21minutes water circulation through the bladder at 17° C. was initiatedwith a commensurate increase in heat flux. At 30 minutes the negativepressure was set to zero causing an immediate drop in heat flux. At 36minutes the negative pressure was reestablished to 40 mm Hg, and theheat flux immediately jumped back to and held at the maximum value. At41 minutes the negative pressure was again removed, with the heat fluxalso falling to the previous lower value. This data demonstrates themechanistic coupling between negative pressure and the enhancement ofheat flow through the skin. This coupling appears to be driven byincreased convection with blood flow through the negative pressuredistended AVAs. The mechanistic action of negative pressure on heattransfer in the skin for the subject technology is verified by thesedata.

Example 4

Heating skin in a peripheral area rich in parasympathetic thermalsensors that effect AVA blood flow produces this result. The results areshown in FIG. 21. Heating the cervical spine of a subject was used toopen vasoconstricted AVAs in glabrous skin of the hand of the subjectwhich caused a large increase in blood perfusion, thereby warming theskin surface.

FIG. 21 shows example data for a test in which a stronglyvasoconstricted state was relaxed by application of focal heating to aselected area along the spine. The total surface area heated was quitesmall to avoid a total heat load that could affect the core temperature.Core temperature was monitored continuously and remained constantthrough the process. A surface thermocouple was mounted on the palm ofone hand when the subject was in a state of strong vasoconstriction thathad existed for more than one hour prior to the experiment. Athermocouple was also mounted on the skin above the spine at the sitewhere heating was applied.

The data show the trigger temperature for this effect is in a narrowrange of above about 40° C. The temperature was restricted to belowabout 44° C. which is near the threshold for causing thermal injury.Thus, the temperature range was from about 40° C. to below about 44° C.

Application of heat to the skin of the cervical spine leads directly toAVA vasodilation in glabrous skin. The vasodilation produced enhancedperfusion of warm blood from the body core, convective heat transfer tothe surrounding tissue, and warming of the surface of the skin as theheat diffuses away from the AVA vascular bed. The mechanistic action ofperipheral heating on AVA vasodilation from the vasoconstricted statefor the subject technology is verified by these data.

Example 5 Warming the Cervical Spine Increases Blood Flow inVasoconstricted AVAs

The application of thermal stimulation via heating to specificperipheral areas of central thermoregulatory control cause a significantincrease in the flow of blood through the AVA vascular structure and theassociated retia venosa. A fiber optic laser Doppler flow probe was usedto measure the change in blood flow in glabrous skin as a function ofthe magnitude of applied surface heating to the cervical spine. Asurface filament thermocouple was used to measure the temperature of theskin on the surface at the cervical spine over which an electric heatingpad was applied.

FIGS. 19 and 20 show the increase in flow of blood through the fingertip and second toe, respectively, in response to the application ofheating on the skin surface at the cervical spine. The data show in bothareas of glabrous skin a direct increment in perfusion followingelevation of the skin temperature at the cervical spine.

Example 6 Warming the Cervical Spine Increases the Surface Temperatureof Initially Vasoconstricted Palmar and Plantar Skin

Heating skin in a peripheral area rich in parasympathetic thermalsensors produces an elevation in the temperature of glabrous skin whenthere is an initial state of vasoconstriction. Heating the cervicalspine of a subject was used to open vasoconstricted AVAs in glabrousskin of the hand and foot of the subject which caused a large increasein blood perfusion, thereby warming the skin surface.

FIGS. 21 and 22 show example data for tests in which a stronglyvasoconstricted state was relaxed by application of focal heating to aselected area along the spine. The total surface area heated was quitesmall to avoid a total heat load that could affect the core temperature.Core temperature was monitored continuously and remained constantthrough the process. A surface thermocouple was mounted on the palm ofone hand, FIG. 21, or to the sole of one foot, FIG. 22, when the subjectwas in a state of strong vasoconstriction that had existed for more thanone hour prior to the experiment. A thermocouple was also mounted on theskin above the spine at the site where heating was applied.

The data show the trigger temperature for this effect is in a narrowrange of above about 39° C. on the surface. The temperature wasrestricted to below about 43° C., which is near the threshold forcausing thermal injury. The effective temperature range for heating theskin surface over the cervical spine to trigger AVA vasodilation rangesfrom about 39° C. to below about 43° C.

Application of heat to the skin of the cervical spine leads directly toAVA vasodilation in glabrous skin. The vasodilation produced enhancedperfusion of warm blood from the body core, convective heat transfer tothe surrounding tissue, and warming of the surface of the skin as theheat diffuses away from the AVA vascular bed. The mechanistic action ofperipheral heating on AVA vasodilation from the vasoconstricted statefor the subject technology is verified by these data.

A fiber optic thermal probe was also used to measure the skin surfacetemperature at the site of perfusion measurement at the finger tip. FIG.23 illustrates the temperature history during this experiment. Initialtemperature of the skin was 24° C., which is indicative of avasoconstricted state as is confirmed by the correspondingly low valueof AVA perfusion. The data for the rate of perfusion through the AVAsshows a steady transition over the first 11 minutes to a vasodilatedstate, with a corresponding rise in the skin temperature byapproximately 8° C. to a new equilibrium value as the increased flow ofwarm blood from the body core through the AVAs caused an interiorconvective source that translated to the progressive warming of the skinsurface. These data show the coupling between AVA perfusion level andskin heat transfer. A further stimulation of blood perfusion at 11minutes causes a greater convection effect between warm blood and theskin tissue, issuing in a further increment in surface temperature. FIG.23 documents the further increment in surface temperature by 2° C. as aresult of the application of negative pressure. The net increase insurface temperature of the skin was 10° C. as a result of the increasein AVA perfusion. The mechanistic action of blood perfusion onconvective heat transfer in the glabrous skin is verified by these data.

Example 7 Warming the Cervical Spine in Conjunction with Cooling thePalmar or Plantar Skin Surfaces Causes a Reduction in Body CoreTemperature

For applications of the devices, systems and methods of the disclosure,from a starting state wherein the AVAs are vasoconstricted, a state ofvasodilation is effected in order to realize the benefits of enhancementof cutaneous circulation. An example is the use of therapeutichypothermia to treat a subject who is suffering an episode of brainischemia that is caused, for example, by stroke, cardiac arrest, ortraumatic brain injury. Such a subject may be in a state of AVAvasoconstriction. At this time, when therapeutic hypothermia is appliedwithin a short time window of efficacy, according to the methods of thedisclosure, a state of AVA vasodilatation is induced and maintainedthroughout the core cooling process.

The palmar surface of the hand and sometimes the plantar surface of thefoot were subjected to cooling by contacting them with a bladder throughwhich chilled water was circulated at the same time that heating wasapplied to the skin overlying the cervical spine. A heat flux gauge andthermocouple were affixed to the palm/sole of the foot in an area whereit contacted the bladder. The protocol consisted of an equilibrationperiod at room temperature, followed by bladder perfusion with water at20° C.

FIG. 24 shows data from these tests. After about the 80^(th) minute ofthe experiment, both neck heating and palmar cooling were in effect.Subsequently, in the 30 minute period roughly between the 80^(th) and110^(th) minutes, the body core of the subject decreased about 0.4degrees Celsius.

As used in the specification, and in the appended claims, the singularforms “a,” “an,” “the,” include plural referents unless the contextclearly dictates otherwise.

The term “comprising” and variations thereof as used herein are usedsynonymously with the term “including” and variations thereof and areopen, non-limiting terms.

Many modifications and other embodiments of the invention set forthherein will come to mind to one skilled in the art to which thisinvention pertains having the benefit of the teachings presented in theforegoing description. Therefore, it is to be understood that theinvention is not to be limited to the specific embodiments disclosed andthat modifications and other embodiments are intended to be includedwithin the scope of the appended claims. Although specific terms areemployed herein, they are used in a generic and descriptive sense onlyand not for purposes of limitation.

1.-53. (canceled)
 54. A method for warming or maintaining the core bodytemperature of a subject, comprising: applying heat to peripheralthermoregulatory control tissue of the subject, wherein the applied heatincreases or maintains perfusion of blood in glabrous tissue of thesubject and applying a warming stimulus to the glabrous tissue therebywarming or maintaining the core body temperature, wherein the heat isapplied to the peripheral thermoregulatory control tissue simultaneouslywith application of the warming stimulus to the glabrous tissue.
 55. Themethod of claim 54, wherein the peripheral thermoregulatory controltissue is located in the cervical spinal region of the subject.
 56. Themethod of claim 54, wherein the peripheral thermoregulatory controltissue is located in the lumbar spinal region of the subject.
 57. Themethod of claim 54, wherein the subject's core body temperature iswarmed or maintained during a surgical procedure.
 58. The method ofclaim 54, wherein the temperature of the thermoregulatory control tissueis raised to between about 39° C. and 43° C.
 59. The method of claim 58,wherein the raised temperature is maintained for at least about oneminute.
 60. The method of claim 58, wherein the raised temperature ismaintained for between about one and five minutes.
 61. The method ofclaim 58, wherein the raised temperature is maintained for at leastabout five minutes.